Molecular and gene expression-based predictors of response to preoperative chemotherapy

Many single-gene molecular markers have been evaluated as predictors of response to specific regimens. However, no reliable and routinely used molecular chemotherapy response predictors exist today. Molecular markers of proliferative activity remain nonspecific predictors of chemotherapy sensitivity in general. Multidrug-resistance transport proteins, p53 gene mutations, and defects in apoptotic pathways remain highly controversial as predictors of response or resistance to particular drugs. To date, the strongest (although still indirect) evidence supporting a molecular predictor of response to a particular regimen comes from a retrospective subset analysis of a variety of studies that showed a link between topoisomerase II amplification and increased sensitivity to anthracyclines. However, the best methodology for determining amplification of topoisomerase II and the appropriate cut-off value to distinguish between individuals with and without amplification have not been established.

Several small studies provided 'proof-of-principle' that the gene expression profile of cancers that are highly sensitive to chemotherapy is different from that of tumors resistant to treatment. Table 1 presents a summary of the current literature. The most exciting possibility implicit to gene expression profiling-based diagnostic tests is that multiple predictors could be applied to a single data set. It is currently technically feasible to perform gene expression profiling on a single biopsy and assess prognosis using a 76-gene, or 70-gene signature, determine the ER and HER-2 status by measuring receptor mRNA levels, predict endocrine sensitivity among the ER-positive patients and estimate the probability of response chemotherapy.

Table 1